Contains Nonbinding Recommendations

Collection of Race and Ethnicity Data in Clinical Trials

Guidance for Industry and Food and Drug Administration Staff

Document issued on October 26, 2016

For questions about this document, contact the FDA Office of Minority Health at 240-402-5084 or

omh@fda.hhs.gov.

U.S. Department of Health and Human Services (HHS) Food and Drug Administration (FDA)

Office of the Commissioner (OC) Office of Minority Health (OMH) Office of Women’s Health (OWH)

Center for Drug Evaluation and Research (CDER) Center for Biologics Evaluation and Research (CBER)

Center for Devices and Radiologic Health (CDRH)

October 2016 Clinical Medical

Contains Nonbinding Recommendations

Preface

Public Comment

You may submit electronic comments and suggestions at any time for Agency consideration to

http://www.regulations.gov. Submit written comments to the Division of Dockets Management,

Food and Drug Administration, 5630 Fishers Lane, Room 1061, (HFA-305), Rockville, MD 20852.

Identify all comments with the docket number FDA-2016-D-3561. Comments may not be acted

upon by the Agency until the document is next revised or updated.

Additional Copies

Additional copies are available from the Internet. You may also send an e-mail request to

omh@fda.hhs.gov to receive a copy of the guidance.

Additional copies are available from the Office of The Commissioner by written request to the

Office of Minority Health, 10903 New Hampshire Ave., WO1, Room 3331A, Silver Spring, MD

20993-0002, by calling 240-402-5084, or by email, omh@fda.hhs.gov.

U.S. Department of Health and Human Services (HHS) Food and Drug Administration (FDA)

Office of the Commissioner (OC) Office of Minority Health (OMH) Office of Women’s Health (OWH)

Center for Drug Evaluation and Research (CDER) Center for Biologics Evaluation and Research (CBER)

Center for Devices and Radiologic Health (CDRH)

October 2016 Clinical Medical

Contains Nonbinding Recommendations

Table of Contents

I. INTRODUCTION ................................................................................................................................. 1

II. SCOPE ................................................................................................................................................... 2

III. BACKGROUND ................................................................................................................................... 4

A. Department of Health and Human Services Report and Guidance ........................................................ 4

B. ICH E5 - Guidance on Ethnic Factors in the Acceptability of Foreign Clinical Data ...........................5

C. National Institutes of Health Initiatives, Revitalization Act .................................................................. 5

D. FDA Regulations, Guidances, and Section 907 of the Food and Drug Administration Safety and Innovation Act of 2012 (FDASIA) ........................................................................................................ 6

Relevance of Population Subgroup Studies .................................................................................. 7

IV. COLLECTING RACE AND ETHNICITY DATA IN CLINICAL TRIALS ....................................... 9

A. Two-Question Format ............................................................................................................................ 9

B. Self-Reporting........................................................................................................................................ 9

C. Ethnicity................................................................................................................................................. 9

D. Race ..................................................................................................................................................... 10

E. Use of More Detailed Racial and Ethnic Categories ........................................................................... 11

F. Use of the term “nonwhite” ................................................................................................................. 12

V. PRESENTATION OF CLINICAL TRIAL RACE AND ETHNICITY DATA .................................. 12

VI. REFERENCES .................................................................................................................................... 13

VII. BIBLIOGRAPHY................................................................................................................................ 13

HHS Policy and Reports .............................................................................................................................. 13

NIH Policies, Reports, and Resources ......................................................................................................... 14

FDA Regulations, Reports, and Legislation ................................................................................................ 14

FDA Guidances for Industry........................................................................................................................ 14

ICH Guidances............................................................................................................................................. 15

Contains Nonbinding Recommendations

Other Sources............................................................................................................................................... 16

NIH PHS Cumulative Inclusion Enrollment Report Form .......................................................................... 16

Collection of Race and Ethnicity Data in Clinical Trials

Guidance for Industry and Food and Drug Administration Staff

1

This guidance represents the current thinking of the Food and Drug Administration (FDA or

Agency) on this topic. It does not establish any rights for any person and is not binding on FDA

or the public. You can use an alternative approach if it satisfies the requirements of the applicable

statutes and regulations. To discuss an alternative approach, please contact the relevant FDA

review division for your medical product.

I. INTRODUCTION

The purpose of this guidance is to provide FDA expectations for and recommendations on

use of a standardized approach for collecting and reporting ra ce and ethnicity data in

submissions for clinical trials for FDA regulated medical products conducted in the United

States and abroad. Using standa rd terminology for age, sex, gender, race, and ethnicity helps

ensure that subpopulation data is collected consistently. The recommended standardized 2

approach is based on the Office of Management and Budget (OMB) Directive 15 and 3

developed in accordance with section 4302 of the Affordable Care Act , the H HS

Implementation Guidance on Data Collection Standards for Race, Ethnicity, Sex, Primary 4

Language, and Disability Status , and the Food and Drug Administration Safety and 5 6

Innovation Act (FDASIA) Section 907 Action Plan . This guidance lists the OMB

1 This guidance has been developed by the Agency-wide Race and Ethnicity Working Group from the Office of the

Commissioner (OC), the Office of Minority Heath (OMH), the Office of Women’s Health (OWH), the Office of

Public Health Strategy and Analysis (OPHSA), the Center for Biologics Evaluation and Research (CBER), the Center

for Drug Evaluation and Research (CDER), and the Center for Devices and Radiological Health (CDRH) of the Food

and Drug Administration (FDA). 2 Office of Management and Budget (OMB) Directive No. 15 Revisions to the Standards for the Classification of

Federal Data on Race and Ethnicity (October 30, 1997), available at

https://www.whitehouse.gov/omb/fedreg_1997standards 3 Patient Protection and Affordable Care Act, Public Law 111-148, Section 4302 (42 U.S.C. § 300kk) (March 23,

2010), available at https://www.gpo.gov/fdsys/pkg/CREC-2009-11-19/pdf/CREC-2009-11-19-pt1-PgS11607-

3.pdf#page=127 4 HHS Implementation Guidance on Data Collection Standards for Race, Ethnicity, Sex, Primary Language, and

Disability Status (October 31, 2011), available at https://aspe.hhs.gov/sites/default/files/pdf/76331/index.pdf 5 Food and Drug Administration Safety and Innovation Act (FDASIA), Public Law 112-144 (July 9, 2012), available at

https://www.congress.gov/bill/112th-congress/senate-bill/3187

Contains Nonbinding Recommendations

categories for race and ethnicity and describes FDA's reasons for recommending the use of

these categories in medical product (drugs, biologics, and devices) applications. In addition,

this guidance recommends a format for collection of race and ethnicity clinical trial data that

are submitted in standardized data sets per the Study Data Tabulation Model7, in the

electronic Common Technical Document (eCTD)8, and as specified in FDA’s Guidance on

providing regulatory submissions in electronic format9 .

This document is intended to provide guidance on:

Meeting the requirements set forth in the 1998 final rule10

regarding presentation of

demographic data on investigational new drug (IND) applications and new drug

applications (NDAs) (known as the “Demographic Rule”) and collection of race and

ethnicity data in biologics license applications (BLAs) and medical device applications

Addressing the FDA Safety and Innovation Act, Section 907 Action Plan6

to improve

demographic subgroup gaps in data quality

FDA's guidance documents, including this guidance, do not establish legally enforceable

responsibilities. Instead, guidances describe the Agency's current thinking on a topic and

should be viewed only as recommendations, unless specific regulatory or statutory

requirements are cited. The use of the word should in Agency guidances means that something

is suggested or recommended, but not required.

II. SCOPE

This document is intended to provide guidance on the collection of race and ethnicity in

clinical trials. This guidance provides clarifying recommendations on the two step collection

process of race and ethnicity data and has been developed in support of the FDASIA 907

Action Plan to improve the completeness and quality of demographic subgroup data. This

guidance replaces the 2005 FDA guidance on Collection of Race and Ethnicity in Clinical

Trials11

.

6 FDA Action Plan To Enhance The Collection and Availability of Demographic Subgroup Data (August 2014) ,

available at http://www.fda.gov/downloads/RegulatoryInformation/Lefislation/SignificantAmendmentstothe

FDCAct/FDASIA/UCM410474.pdf 7

CDISC standardized Study Data Tabulation Model (SDTM), Analysis Data Model (ADaM), Operational Data Model

(ODM), http://www.cdisc.org/system/files/members/standard/study_data_tabulation_model_v1_4.pdf 8

Providing Regulatory Submissions in Electronic Format – Certain Human Pharmaceutical Product Applications and

Related Submissions Using the eCTD Specifications: Guidance for Industry (May 2015), available at

http://www.fda.gov/Drugs/DevelopmentApprovalProcess/FormsSubmissionRequirements/ElectronicSubmissions/uc

m153574.htm 9

Providing Regulatory Submissions In Electronic Format - Standardized Study Data: Guidance for Industry

(December 2014), available at http://www.fda.gov/downloads/Drugs/.../Guidances/UCM292334.pdf 10

63 FR 6854 (February 11, 1998) (codified at 21 CFR 312.33(a)(2) and 21 CFR 314.50(d)(5)) ,

https://www.gpo.gov/fdsys/pkg/FR-1998-02-11/pdf/98-3422.pdf 11

Collection of Race and Ethnicity in Clinical Trials (September 2005),

http://www.fda.gov/downloads/RegulatoryInformation/Guidances/ucm126396.pdf

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For drugs, the Demographic Rule requires IND holders to tabulate in their annual report the

number of participants enrolled in clinical trials by age, race, and gender12

and requires

sponsors of NDAs to include summaries of effectiveness and safety data for important

demographic subgroups, including racial subgroups13

. FDA also strongly recommends the

collection and reporting of ethnicity data (Hispanic-Latino/not Hispanic-Latino) consistent

with OMB standards and guidelines2 .

This guidance is also intended to help applicants in preparing BLAs.

For medical devices, FDA also recommends application sponsors collect ethnicity and race data

in accordance with the OMB recommendations2, the information collection standards discussed

in this guidance document and, when finalized, the Center for Devices and Radiologic Health

(CDRH) and Center for Biologics Evaluation and Research (CBER) Age/Race/Ethnicity draft

guidance document14

.

FDA expectations are that sponsors e nroll participants who reflect the demographics for 13

clinically relevant populations with regard to age, gender, race, a nd ethnicity . A pla n to

address inclusion of clinically relevant subpopulations should be submitted for discussion to

the Agency at the earliest phase of development and, for drugs and biologics, no later than the

end of the phase 2 meeting. Inadequate participation and/or data analyses from clinically

relevant subpopulations can lead to insufficient information pertaining to medical product

safety and effectiveness for product labeling. P atient characteristics such as age, sex, gender,

geographic location (e.g. rural), emotional, physical, sensory, and cognitive capabilities can

often be important variables when evaluating medical product safety and efficacy. However,

these will not be addressed within this guidance.

This guidance does not address the level of participation of racial and ethnic groups in clinical

trials. For questions related to the level of participation or the size of a trial, sponsors should

12 The terms sex and gender have been used interchangeably in some FDA documents. However, according to a 2001

consensus report from the Institute of Medicine (Institute of Medicine, Committee on Understanding the Biology of

Sex and Gender Differences. Exploring the Biological Contributions to Human Health: Does Sex Matter?, National

Academy of Sciences, 2001), the terms have distinct definitions which should be used consistently to describe

research results. Sex refers to the classification of living things, generally as male or female according to their

reproductive organs and functions assigned by chromosomal complement. Gender refers to a person’s self-

representation as male or female, or how that person is responded to by social institutions based on the individual’s

gender presentation. Gender is rooted in biology, and shaped by environment and experience. Because of underlying

differences in the statutes and regulations referenced in this policy, the terms “gender” and “sex” have both been used

in this document in accordance with the source material referenced. 13

21 CFR § 312.33(a)(2) (April 1, 2015). See also 21 CFR § 314.50(d)(5)(v) and (vi)(a) regarding demographic data

submission in NDAs, available at http://www.ecfr.gov/cgi-bin/textidx?SID=41aa69ac1cd29cf7eb1c3b24d764f310

&mc=true&node=se21.5.314_150&rgn=div8 14

Draft Guidance: Evaluation and Reporting of Age, Race, and Ethnicity Data in Medical Device Clinical Studies (June

2016), available at http://www.fda.gov/downloads/MedicalDevices/DeviceRegulationandGuidance/

GuidanceDocuments/UCM507278.pdf. Draft guidances are included for completeness only. As draft documents,

they are not intended to be implemented until published in final form.

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Contains Nonbinding Recommendations

consult with the review division of the appropriate centers and office15 16 17

for guidance on

clinical trial design and demographic sub-groups prior to the start of a trial.

III. BACKGROUND

Over recent decades the Agency’s views, as well as those of the medical community, have evolved

regarding the collection of race and ethnicity information in clinical studies.

Prior to developing the recommendations set forth in this guidance, FDA publicly sought input

from a variety of experts and stakeholders regarding the study and evaluation of age, race, and

ethnicity in clinical studies for medical products. On April 1, 2014, FDA convened a public 18 19

hearing for feedback on the findings of the FDASIA 907 Report, to obtain input on the issues

and challenges associated with the collection, analysis, and availability of demographic subgroup

data (i.e., a ge, sex, race, and ethnicity) in applications for approval of FDA‐regulated medical 18 20

products. FDA also opened a public docket for further input . On April 9, 2015 and December 2, 21

2015 , various government agencies, physician professional societies, and patient advocacy groups

participated in public workshops to discuss strategies for ensuring diversity, inclusion, and

meaningful participation in clinical trials. This guidance reflects the concerns and

recommendations generated in these and other public fora. The following is a brief history of the

adoption of the OMB categories for reporting of race and ethnicity data by the Department of

Health and Human Services (HHS), the National Institutes of Health (NIH) and FDA.

A. Department of Health and Human Services Report and Guidance In 1999, HHS issued a report, Improving the Collection and Use of Racial and Ethnic Data

in HHS22

. The report describes HHS policy on collecting and reporting data on race and

15 Center for Devices and Radiological Health Organization,

http://www.fda.gov/AboutFDA/CentersOffices/OrganizationCharts/ucm347835.htm 16

CBER Offices and Divisions,

http://www.fda.gov/AboutFDA/CentersOffices/OfficeofMedicalProductsandTobacco/CBER/ucm122875.htm 17

CDER Offices and Divisions,

http://www.fda.gov/AboutFDA/CentersOffices/OfficeofMedicalProductsandTobacco/CDER/ucm075128.htm 18

Notice of Public Hearing: Action Plan for the Collection, Analysis, and Availability of Demographic Subgroup Data

in Applications for Approval of Food and Drug Administration-Regulated Medical Products, 79 FR 42, 12134

(March 4, 2014), available at https://www.federalregister.gov/articles/2014/03/04/2014-04625/action-plan-for-the-

collection-analysis-and-availability-of-demographic-subgroup-data-in 19

http://www.fda.gov/downloads/RegulatoryInformation/Legislation/SignificantAmendmentstotheFDCAct/FDASIA/U

CM397391.pdf (April 1, 2014) 20

Institute of Medicine Workshop: Strategies for Ensuring Diversity, Inclusion, and Meaningful Participation in

Clinical Trials (April 9, 2015), available at

http://www.nationalacademies.org/hmd/Activities/SelectPops/HealthDisparities/2015-APR-09.aspx 21

FDA Public Meeting: Clinical Trials-Assessing Safety and Efficacy for Diverse Populations, 80 FR 210, 66909

(October 30, 2015), available at https://www.federalregister.gov/articles/2015/10/30/2015-27728/clinical-trials-

assessing-safety-and-efficacy-for-diverse-populations-public-meeting-request-for 22

Improving the Collection and Use of Racial and Ethnic Data in HHS (December 1, 1999), available at

https://aspe.hhs.gov/report/improving-collection-and-use-racial-and-ethnic-data-hhs

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Contains Nonbinding Recommendations

ethnicity for HHS programs. The report asks for the inclusion of race and ethnicity

categories in HHS funded and sponsored data collection and reporting systems in all HHS

programs, including in both health and human services. The policy was developed to (1)

help monitor HHS programs, (2) determine whether Federal funds are being used in a

nondiscriminatory manner, and (3) promote the availability of standard race and ethnicity

data across various agencies to facilitate HHS responses to major health and human 4

services issues. This policy, updated in 2011 , clearly states that the minimum standard 2

categories in OMB Policy Directive 15 should be used when collecting and reporting data 23

in HHS data systems or reporting HHS funded statistics .

B. ICH E5 - Guidance on Ethnic Factors in the Acceptability of

Foreign Clinical Data

In 1999, as part of an international effort by the United States and others to harmonize

technical requirements for pharmaceutical drug development and regulation (the

International Conference on Harmonization (ICH)), the FDA published a guidance entitled

E5 Guidance on Ethnic Factors in the Acceptability of Foreign Clinical Data24

(63 FR

31790, June 10, 1998), that described how clinical data collected in one region could be

used in the registration or approval of a drug or biological product in another region, taking

into account the influence of ethnic factors. The E5 guidance defines ethnic factors that

affect response in terms of both intrinsic and extrinsic issues. Because differences in ethnic

factors have the potential to affect responses in some subpopulations, the E5 guidance

provides a general framework for evaluating medicines with regard to their sensitivity to

ethnic factors. In particular, the Question and Answer Addendum to E5 introduces the

multi-regional clinical trial study design as one means to evaluate treatment response

heterogeneity and extrapolation. Multi-regional clinical trials may present special situations

for the collection and self-reporting of race and ethnicity.

C. National Institutes of Health Initiatives, Revitalization Act 25

In 1993, the National Institutes of Health (NIH) Revitalization Act directed NIH to

establish guidelines for including women and minorities in NIH-sponsored clinical 26 27

research . In 2001, NIH was directed to ensure that women and minorities were

included as participants, unless their exclusion was justified due to circumstances specified

by NIH guidelines. Furthermore, clinical trials were to be designed and carried out in a

23 On September 21, 2016, HHS issued the final rule on Clinical Trials Registration and Results Information

Submission (42 CFR Part 11). When fully implemented, the final rule will require the submission of race and

ethnicity information with summary results information, if it is collected during the trial. Available at

https://www.gpo.gov/fdsys/pkg/FR-2016-09-21/pdf/2016-22129.pdf 24

E5 Guidance on Ethnic Factors in the Acceptability of Foreign Clinical Data, available at

http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Efficacy/E5_R1/Step4/E5_R1__Guideline.

pdf 25

NIH Revitalization Act of 1993, (PL 103-43) (June 10, 1993), available at https://grants.nih.gov/grants/olaw/pl103-

43.pdf 26

NIH Revitalization Act of 1993, (PL 103-43), Subtitle B (June 10, 1993), available at

http://orwh.od.nih.gov/about/pdf/NIH-Revitalization-Act-1993.pdf 27

NIH Policy and Guidelines on The Inclusion of Women and Minorities as Subjects in Clinical Research (October

2001), available at https://grants.nih.gov/grants/funding/women_min/guidelines_amended_10_2001.htm

5

Contains Nonbinding Recommendations

manner that would elicit information across genders and diverse racial and ethnic

subgroups to examine differential effects on such groups.

NIH guidelines stipulate that when proposing a phase 3 clinical trial, evidence must be

reviewed to establish whether or not there are potentially clinically important sex- and

racial/ethnic-based differences in the anticipated effects of the intervention. If previous

studies support the existence of significant differences, the primary questions and design of

the trial must specifically accommodate this. For example, if men and women are thought

to respond differently to an intervention, then the phase 3 clinical trial must be designed to

answer two separate primary questions, one for men, and the other for women. When prior

studies support no significant differences for either sex/gender or racial/ethnic subgroups

with a given intervention, then sex/gender and racial/ethnic status will not be required as

subject selection criteria, although the inclusion and analysis by gender and racial/ethnic

groups is strongly encouraged. When prior studies neither support nor negate significant

differences, then the design of the phase 3 clinical trial will be required to include sufficient

and appropriate entry of sex/gender and racial/ethnic participants so that valid analysis of

the intervention effects can be performed. However, the trial will not be required to provide

high statistical power for these comparisons.

D. FDA Regulations, Guidances, and Section 907 of the Food and

Drug Administration Safety and Innovation Act of 2012

(FDASIA)

In 1997, OMB issued its revised recommendations for the collection and use of race and

ethnicity data by Federal agencies (Policy Directive 15)2 . OMB stated that its race and

ethnicity categories were not anthropologically or scientifically-based designations, but

instead were categories that described the sociocultural construct of our society.

As outlined in FDA’s 2005 Guidance on Collection of Race and Ethnicity in Clinical

Trials11

, FDA recommended the use of the standardized OMB race and ethnicity categories

for data collection in clinical trials for two reasons. First, the use of the recommended OMB

categories will help ensure consistency in demographic subset analyses in applications

submitted to FDA13

and in data collected by other government agencies. Second,

consistency in these categories may make the demographic subset analysis more useful in

evaluating potential differences in the safety and effectiveness of medical products among

population subgroups. To assess potential subgroup differences in a meaningful way, it is

important to use uniform, standard methods of defining racial and ethnic subgroups.

FDA regulations require sponsors of Investigational New Drugs (INDs)28

to report the total

number of subjects initially planned for inclusion in the study; the number entered into the

study to date, tabulated by age group, gender, and race; the number whose participation in

the study was completed as planned; and the number who dropped out of the study for any

28 21 CFR § 312.33(a)(2), available at

https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?fr=312.33

6

Contains Nonbinding Recommendations

reason. FDA regulations for NDAs require sponsors to present a summary of safety and

effectiveness data by demographic subgroups (age, sex, race, and other subgroups as

appropriate)29

, as well as an analysis of whether modifications of dose or dosage intervals

are needed for specific subgroups30

. FDA recommends the identification of a subject’s race

and/or ethnicity in such summaries.

Section 907 of FDASIA directed the Agency to develop a report31 “addressing the extent to

which clinical trial participation and the inclusion of safety and effectiveness data by

demographic subgroups, including sex, age, race, and ethnicity, is included in applications

submitted to the Food and Drug Administration.” Section 907 also directed FDA to develop

an action plan outlining “recommendations for improving the completeness and quality of

analyses of data on demographic subgroups in summaries of product safety and

effectiveness data and in labeling; on the inclusion of such data, or the lack of availability of

such data, in labeling; and on improving the public availability of such data to patients,

health care providers, and researchers.” In support of that Action Plan, FDA has developed

this guidance as one of the actions to improve the completeness and quality of demographic

subgroup data

Relevance of Population Subgroup Studies

Differences in response to medical products have already been observed in racially

and ethnically distinct subgroups of the U.S. population32

. These differences may be

attributable to intrinsic factors (e.g., genetics, metabolism, elimination), extrinsic

factors (e.g., diet, environmental exposure, sociocultural issues), or interactions

between these factors (Huang 2008)33

.

An FDA review of drug approvals between 2008 and 2013 found that approximately

one-fifth of new drugs demonstrated some differences in exposure and/or response

across racial/ethnic groups (Ramamoorthy 2015)34

. For example, racial differences

29 21 CFR § 314.50(d)(5)(v) and (vi)(a) (October 2015). See also Integrated Summary of Effectiveness Guidance for

Industry, available at http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/

guidances/ucm079803.pdf 30

Under 21 CFR 314.101(d)(3), the Agency may refuse to file an NDA if it is incomplete because it does not contain

information required by 21 CFR 314.50. Thus, if there is an inadequate evaluation for safety and/or effectiveness of

the population intended to use the drug, including pertinent subsets, such as gender, age, and racial subsets the

Agency may refuse to file the application. See FDA's Manual of Policies and Procedures, Office of New Drugs, Good

Review Practice: Refuse to File (October 10, 2013), available at http://www.fda.gov/downloads/AboutFDA/

CentersOffices/OfficeofMedicalProductsandTobacco/CDER/ManualofPoliciesProcedures/UCM370948.pdf 31

FDA Report Collection, Analysis, and Availability of Demographic Subgroup Data for FDA-Approved Medical

Products (August 2013), available at http://www.fda.gov/downloads/RegulatoryInformation/Legislation/

SignificantAmendmentstotheFDCAct/FDASIA/UCM365544.pdf 32

In fact, in June of 2005, FDA approved BiDil, the first drug approved by the Agency to treat a disease in patients

identified by race. The drug was approved for the treatment of heart failure in Black patients. The sponsor

conducted two trials in the general population that failed to show a benefit, but suggested a benefit of BiDil in Black

patients. The company then studied the drug in 1,050 self-identified Black patients and it was shown to be safe and

effective. 33 Huang SM & Temple R, 2008, “Is this the drug or dose for you? Impact and consideration of ethnic factors in global

drug development, regulatory review, and clinical practice,” Clin Pharmacol Ther, 84: 287 -294 34

Ramamoorthy A, Pacanowski MA, Bull, J, and Zhang L, 2015, "Racial/ethnic differences in drug disposition and

response: review of recently approved drugs," Clin Pharmacol Ther, 97: 263-273.

7

Contains Nonbinding Recommendations

in skin structure and physiology can affect response to dermatologic and topically 35

applied products (Taylor 2002) . Mortality rates of patients on dialysis have been 36

shown to differ across race and ethnicity groups . Several studies have also shown

that Blacks respond less well to several classes of antihypertensive agents (beta 37

blockers and angiotensin converting enzyme (ACE) inhibitors) (Exner 2001 and 38

Yancy 2001 ). For cytochrome P450 2D6 (CYP2D6), an important enzyme that

metabolizes drugs belonging to a variety of therapeutic areas such as antidepressants,

antipsychotics, and beta blockers, the frequency of poor metabolizers is higher in 39

Whites (7-10%) and Blacks or African Americans (3-8%) than in persons of Asian 40 41

heritage (Xie 2001) . The incidence of anticonvulsant carbamazepine -induced

Stevens-Johnson syndrome-toxic epidermal necrolysis has shown a strong 42

association with HLA-B*1502 (Chung 2004 ), an allele that is highly prevalent in

Asian populations (particularly Chinese) when compared to non-Asian populations 43 44

(Hung 2006 and Alfir evic 2006 ).

Collecting data on race and/or ethnicity is critical to identifying population-specific

signals. As illustrated above, genetic studies may explain the basis for observed

differences in pharmacokinetics, efficacy, or safety across racial or ethnic subgroups,

and FDA has recommended collection of DNA samples in clinical trials for such

purposes 45

. FDA has also published guidance on enrichment strategies for selecting

participants for clinical trials based on prognostic or predicative biomarkers (such as

genotype)46

.

35 Taylor S, 2002, “Skin of Color: Biology, Structure, Function, and Implications for Dermatologic Disease,” Journal

of American Academy of Dermatology, 46: S41-62 36

Yan, Guofen, et al., 2013, "The relationship of age, race, and ethnicity with survival in dialysis patients," Clinical

Journal of the American Society of Nephrology, 8.6: 953-961. 37

Exner D, Dries D, Donamski M, and Cohn J, 2001, “Lesser Response to Angiotensin Converting-Enzyme Inhibitor

Therapy in Black as Compared with White Patients With Left Ventricular Dysfunction,” N Engl J Med, 344: 1351-

1357 38

Yancy C, Fowler M, Colucci W, Gilbert E, Bristow M, et al., 2001, “Race and the Response to Adrenergic Blockade

with Carvedilol in Patients with Chronic Heart Failure,” N Engl J Med, 344: 1358-1365. 39

The terms used in this guidance to describe the various racial and ethnic groups are those used by OMB 40

Xie H, Kim R, Wood A, and Stein C, 2001, “Molecular Basis of Ethnic Differences in Drug Disposition and

Response,” Annu Rev Pharmacol Toxicol, 41: 815-850. 41

Carbamazepine postmarket drug safety and information (December 12, 2007), available at

http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm124718.htm 42

Chung, WH, Hung, SI, Hong, HS, Hsih, MS, Yang, LC, et al, 2004, “A Marker for Stevens-Johnson Syndrome,”

Nature, 428: 486. 43 Hung SI, Chung WH, Jee SH, Chen WC, Chang YT, et al, 2006, “Genetic Susceptibility to Carbamazepine -Induced

Cutaneous Adverse Drug Reactions,” Pharmacogenetics and Genomics, 16: 297-306 44 Alfirevic A, Jorgensen AL, Williamson PR, Chadwick DW, Park BK, Pirmohamed M. 2006, “HLA -B locus in

Caucasian patients with carbamazepine hypersensitivity,” Pharmacogenomics, 7:813-818 45

Guidance for Industry: Clinical Pharmacogenomics: Premarket Evaluation in Early-Phase Clinical Studies and

Recommendations for Labeling (January 2013), available at

http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm337169.pdf 46

Draft Guidance: Enrichment Strategies for Clinical Trials to Support Approval of Human Drugs and Biological

Products (December 2012), available at

http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm332181.pdf

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Contains Nonbinding Recommendations

IV. COLLECTING RACE AND ETHNICITY DATA IN

CLINICAL TRIALS

The classifications discussed below provide a minimum standard for maintaining, collecting, and

presenting data on race and ethnicity for Federal reporting purposes. Consistent with OMB

Policy Directive 15, the categories in this classification are social-political constructs and should

not be interpreted as being scientific or anthropological in nature. They are not to be used as

determinants of eligibility for participation in any Federal program. The standards have been

developed to provide a common framework for uniformity and consistency in the collection and

use of data on race and ethnicity by Federal agencies.

The recommendations in this section reflect the Agency's commitment to and expectations for more consistent demographic subgroup data collection. For studies conducted both inside and outside the United States, the Agency recommends the following process, which is based on the current OMB Directive for collecting racial and ethnic data. These recommendations are also consistent with the format for collecting race and ethnicity data set forth in NIH guidance

47 .

A. Two-Question Format

In order to be consistent with OMB and other recommended best practices, FDA

recommends using the two-question format for requesting race and ethnicity information,

with the ethnicity question preceding the question about race. Example:

Question 1 (answer first): Do you consider yourself Hispanic/Latino or not

Hispanic/Latino?

Question 2 (answer second): Which of the following five racial designations best

describes you? More than one choice is acceptable.

B. Self-Reporting

FDA recommends that trial participants self-report race and ethnicity information and

those individuals be permitted to designate a multiracial identity. When the collection of

self-reported designations is not feasible (e.g., because of the subject’s inability to

respond), we recommend that the information be requested from a first-degree relative or

other knowledgeable source. Race and ethnicity should not be assigned by the study team

conducting the trial.

C. Ethnicity

For ethnicity, we recommend the following minimum choices be offered:

47 NIH Policy and Guidelines on The Inclusion of Women and Minorities as Subjects in Clinical Research (Amended,

October 2001), available at https://grants.nih.gov/grants/funding/women_min/guidelines_amended_10_2001.htm

9

Contains Nonbinding Recommendations

Hispanic or Latino: A person of Cuban, Mexican, Puerto Rican, South or Central

American, or other Spanish culture or origin, regardless of race. The term, “Spanish origin,”

can be used in addition to “Hispanic or Latino.”

Not Hispanic or Latino

D. Race

For race, we recommend the following minimum choices be offered:

American Indian or Alaska Native: A person having origins in any of the original

peoples of North and South America (including Central America), and who maintains

tribal affiliation or community attachment.

Asian: A person having origins in any of the original peoples of the Far East, Southeast

Asia, or the Indian subcontinent, including, for example, Cambodia, China, India, Japan,

Korea, Malaysia, Pakistan, the Philippine Islands, Thailand, and Vietnam.

Black or African American: A person having origins in any of the black racial

groups of Africa. Terms such as “Haitian” or “Negro” can be used in addition to

“Black or African American.”

Native Hawaiian or Other Pacific Islander: A person having origins in any of the

original peoples of Hawaii, Guam, Samoa, or other Pacific Islands.

White: A person having origins in any of the original peoples of Europe, the Middle East,

or North Africa.

We recommend offering an option of selecting one or more racial designations or

additional subgroup designations. Recommended forms for the instruction accompanying

the multiple response questions are “Mark one or more” and “Select one or more.”

Sponsors should report the number of respondents in each racial category who self-

reported as Hispanic or Latino. When aggregate data are presented, data producers should

provide the number of respondents who marked (or selected) only one category, separately

for each of the five racial categories. In addition to these numbers, data producers are

encouraged to provide the detailed distributions, including all possible combinations of

multiple responses to the race question. If data on multiple responses are collapsed, at a

minimum the total number of respondents reporting “more than one race” shall be made

available (see attached NIH PHS Inclusion Enrollment Report form48

)

48 NIH PHS Inclusion Enrollment Report Form (March 25, 2015), available at

http://grants.nih.gov/grants/forms/inclusion-enrollment-report.pdf

10

E. Use of More Detailed Racial and Ethnic Categories

In certain situations, as recommended in OMB Policy Directive 15, more detailed race and

ethnicity information may be desired. For example, for clinical trials conducted outside

the United States, FDA recognizes that the recommended categories for race and ethnicity

were developed in the United States and that these categories may not adequately describe

racial and ethnic groups in foreign countries. Furthermore, White can reflect origins in

Europe, the Middle East, or North Africa; Asian can reflect origins from areas ranging

from India to Japan.

In situations where appropriate, FDA recommends using more detailed categories by

geographic region to provide sponsors the flexibility to adequately characterize race and

ethnicity. As outlined in the 2011 HHS Implementation Guidance on Data Collection

Standards for Race, Ethnicity, Sex, Primary Language, and Disability Status4, if additional

granularity or more detailed characterizations of race or ethnicity are collected to enhance

understanding of the trial participants, FDA recommends these characterizations be

traceable to the five minimum designations for race and two designations for ethnicity

listed in sections D and C above. Example (from the above referenced 2011 HHS

Guidance4):

Ethnicity Data Standard

Are you Hispanic, Latino/a, or of Spanish origin? (One or more categories may be selected)

a. ____No, not of Hispanic, Latino/a, or Spanish origin

b. ____Yes, Mexican, Mexican American, Chicano/a

c. ____Yes, Puerto Rican

d. ____Yes, Cuban

e. ____Yes, Another Hispanic, Latino/a or Spanish origin

These categories roll up to the

Hispanic or Latino category of

the OMB standard

Race Data Standard

What is y our race? (One or more categories may be selected)

a. ____White

b. ____Black or African American

c. ____American Indian or Alaska Native

d. ____Asian Indian

e. ____Chinese

f. ____ Filipino

g. ____Japanese

h. ____Korean

i. ____ Vietnamese

j. ____ Other Asian

k. ____Native Hawaiian

l. ____ Guamanian or Chamorro

m. ___ Samoan

n. ____Other Pacific Islander

These categories are part of the

current OMB standard

These categories roll up to the Asian

category of the OMB standard

These categories roll-up to the Native Hawaiian or

Other Pacific Islander category of the OMB standard

Contains Nonbinding Recommendations

11

Contains Nonbinding Recommendations

Where concerns exist in the representation of race or ethnicity categories, sponsors

are encouraged to discuss the race or ethnicity issues with the appropriate review

division.

F. Use of the term “nonwhite”

The term “nonwhite” is not acceptable for use in the presentation of Federal Government

data. It should not be used in publication or text of any report.

V. PRESENTATION OF CLINICAL TRIAL RACE AND

ETHNICITY DATA

For INDs, NDAs, and BLAs, we recommend the submission of tabulated demographic data 10 13

based on the Demographic Rule for all clinical trials using the characterizations of race

and ethnicity described in this guidance. Beginning in May 2017, CDER and CBER will

require marketing applications to be submitted electronically49

. CDER and CBER use the

eCTD as the standard for their electronic applications. When submitting an electronic

application, presentation of demographic data is described in ICH M4E eCTD Guidance

(section 2.7.4.1.3 and table 2.7.4.2)50

, which suggests a tabular display of demographic

characteristics (e.g., age, sex, race) by treatment group (e.g., active drug, placebo)51

. With

regard to the description of race and ethnicity, the categories that are suggested previously in

this document (Section IV) provide more detail than those suggested in the ICH M4E eCTD

guidance. FDA recommends that sponsors provide the level of detail described in Section IV

of this guidance. For relevant device submissions, we recommend following the guidance

presented here and, when finalized, the recommendations in the draft guidance documents

Evaluation and Reporting of Age, Race, and Ethnicity Data in Medical Device Clinical

Studies14

.

49 Providing Regulatory Submissions in Electronic Format – Certain Human Pharmaceutical Product Applications and

Related Submissions Using the eCTD Specifications: Guidance for Industry (May 2015), available at

http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM333969.pdf 50

Revision of M4E Guideline on Enhancing the Format and Structure of Benefit-Risk Information on ICH Efficacy –

M4E(R2) (June 15, 2016), available at

http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/CTD/M4E_R2_Efficacy/M4E_R2__Step_4.pdf 51

12

The ICH M4 eCTD document suggests specific kinds of demographic information to be collected as a part of a

clinical trial, but does not provide rigid specifications on how the data should be presented, noting, for example, that

“if relative exposure of demographic groups in the controlled trials differ from the overall exposure, it may be useful

to provide separate tables.” Choices of how best to summarize demographic data depend on the nature of the data to

be conveyed. For some trials, it may be useful to show the distribution of one demographic characteristic within a

second demographic (e.g., the age distribution of men and women enrolled in a set of controlled trials).

Contains Nonbinding Recommendations

VI. REFERENCES

Alfirevic A, Jorgensen AL, Williamson PR, Chadwick DW, Park BK, Pirmohamed M. 2006, “HLA-B locus in Caucasian patients with carbamazepine hypersensitivity,”Pharmacogenomics, 7:813-818

Chung, WH, Hung, SI, Hong, HS, Hsih, MS, Yang, LC, et al, 2004, “A Marker for Stevens-Johnson Syndrome,” Nature, 428: 486.

Exner D, Dries D, Donamski M, and Cohn J, 2001, “Lesser Response to Angiotensin-

Converting-Enzyme Inhibitor Therapy in Black as Compared with White Patients With Left Ventricular Dysfunction,” N Engl J Med, 344: 1351-1357.

Huang SM & Temple R, 2008, “Is this the drug or dose for you? Impact and consideration of

ethnic factors in global drug development, regulatory review, and clinical practice,” Clin

Pharmacol Ther, 84: 287-294

Hung SI, Chung WH, Jee SH, Chen WC, Chang YT, et al, 2006, “Genetic Susceptibility

to Carbamazepine-Induced Cutaneous Adverse Drug Reactions,” Pharmacogenetics and

Genomics, 16: 297-306.

Ramamoorthy A, Pacanowski MA, Bull, J, and Zhang L, 2015, "Racial/ethnic differences in drug disposition and response: review of recently approved drugs," Clin Pharmacol Ther, 97: 263-273.

Taylor S, 2002, “Skin of Color: Biology, Structure, Function, and Implications for Dermatologic Disease,” Journal of American Academy of Dermatology, 46: S41-62.

Xie H, Kim R, Wood A, and Stein C, 2001, “Molecular Basis of Ethnic Differences in DrugDisposition and Response,” Annu Rev Pharmacol Toxicol, 41: 815-850.

Yan, Guofen, et al., 2013, "The relationship of age, race, and ethnicity with survival in dialysis

patients," Clinical Journal of the American Society of Nephrology, 8.6: 953-961.

Yancy C, Fowler M, Colucci W, Gilbert E, Bristow M, et al., 2001, “Race and the Response to

Adrenergic Blockade with Carvedilol in Patients with Chronic Heart Failure,” N Engl J

Med, 344: 1358-1365.

VII. BIBLIOGRAPHY

HHS Policy and Reports

13

Contains Nonbinding Recommendations

Policy Statement on Inclusion of Race and Ethnicity in DHHS Data Collection Activities

(October 24, 1997)

Improving the Collection and Use of Racial and Ethnic Data in HHS (December 1, 1999)

US Department of HHS implementation guidance on data collections standards for race,

ethnicity, sex, primary language, and disability status (October 31, 2011)

NIH Policies, Reports, and Resources

NIH Revitalization Act of 1993, Subtitle B (PL 103-43) (June 10, 1993)

NIH policy on reporting ra ce and ethnicity data: Subjects in clinical research (August 8, 2001)

NIH Guidelines on the Inclusion of Women and Minorities as Subjects in Clinical

Research (October 2001)

Use of new inclusion management system required as of October 17, 2014 (October 2,

2014)

NIH PHS Inclusion Enrollment Report Form (March 25, 2015)

NIH Policy Implementation Page: Inclusion of Women and Minorities as Participants

in Research Involving Human Subjects

FDA Regulations, Reports, and Legislation

Food and Drug Administration Modernization Act of 1997 (Public Law 105-115, November 21, 1997)

Investigational New Drug Applications and New Drug Applications (21 CFR 312 and

314, February 11, 1998)

Food and Drug Administration Amendments Act (FDAAA) of 2007, Public Law No. 110-85 Section 901 of the Federal Food, Drug, and Cosmetic Act (September 2009)

FDA Safety and Innovation Act (Public Law No. 112-114 (February 9, 2012)

FDA Report Collection, Analysis, and Availability of Demographic Subgroup Data for FDA-Approved Medical Products (August 2013)

FDA Action Plan To Enhance The Collection and Availability of Demographic Subgroup Data (August 2014)

Food and Drug Administration (FDA), 1998, “Investigational New Drug Applications

and New Drug Applications (21 CFR 314.50(b), April 1, 2015)

FDA Guidances for Industry

Guideline for the Study and Evaluation of Gender Differences in the Clinical Evaluation

of Drugs (July 1993)

General Considerations for the Clinical Evaluation of Drugs (February 1997)

Guidance on IDE Policies and Procedures (January 1998)

14

Contains Nonbinding Recommendations

Format and Content of the Clinical and Statistical Sections of an Application (July 1998)

M4E: The CTD- Efficacy (August 2001)

Content and Format for Geriatric Labeling (October 2001)

Pharmacokinetics in Patients with Impaired Hepatic Function: Study Design, Data

Analysis, and Impact on Dosing and Labeling (May 2003)

Collection of Race and Ethnicity Data in Clinical Trials (September 2005)

Clinical Studies Section of Labeling for Human Prescription Drugs and Biological

Products - Content and Format (January 2006)

Adverse Reactions Section of Labeling for Human Prescription Drugs and Biological

Products - Content and Format (January 2006)

Clinical Pharmacogenomics: Premarket Evaluation in Early-Phase Clinical Studies and

Recommendations for Labeling (January 2013)

Design Considerations for Pivotal Clinical Investigations for Medical Devices

(November 2013)

Evaluation of Sex-Specific Data in Medical Device Clinical Studies (August 2014)

General Clinical Pharmacology Considerations for Pediatric Studies for Drugs and

Biological Product (December 2014)

Providing Regulatory Submissions In Electronic Format - Standardized Study Data

(December 2014)

Providing Regulatory Submissions in Electronic Format —Certain Human

Pharmaceutical Product Applications and Related Submissions Using the eCTD

Specifications (May 2015)

Integrated Summary of Effectiveness Guidance for Industry (October 2015)

Human Immunodeficiency Virus-1 Infe ction: Developing Antiretroviral Drugs for

Treatment (November 2015)

Study Data Technical Conformance Guide (March 2016)

Draft Guidance: Diabetes Mellitus: Developing Drugs and Therapeutic Biologics for

Treatment and Prevention (February 2008)

Draft Guidance: Pharmacokinetics in Patients with Impaired Renal Function: Study

Design, Data Analysis and Impact on Dosing and Labeling (March 2010)

Draft Guidance: Drug Interaction Studies — Study Design, Data Analysis, Implications,

for Dosing and Labeling Recommendations (February 2012)

Draft Guidance: Enrichment Strategies for Clinical Trials to Support Approval of Human

Drugs and Biological Products (December 2012)

Draft Guidance: Chronic Hepatitis C Virus Infection: Developing Direct-Acting Antiviral

Drugs for Treatment (May 2016)

Draft Guidance: Evaluation and Reporting of Age, Race, and Ethnicity Data in Medical

Device Clinical Studies (June 2016)

ICH Guidances

ICH, E7 Studies in Support of Special Populations: Geriatrics (June 24, 1993)

ICH, E4 Dose Response Information to Support Drug Registration ( March 1994)

ICH, E5 Ethnic Factors in the Acceptability of Foreign Data (February 5, 1998)

15

Contains Nonbinding Recommendations

ICH, E11 Clinical Investigation of Medicinal Products in the Pediatric Population (July

20, 2000)

ICH, M4 Common Technical Document for the Registration of Pharmaceuticals for

Human Use (January 13, 2004)

Other Sources

General Accounting Office, FDA Needs to Ensure More Study of Gender Differences in Prescription Drug Testing, GAO/HFD-93-17 (October 1992)

Office of Management and Budget: Standards for the Classification of Federal Data on Race and Ethnicity (June 9, 1994)

Office of Management and Budget (OMB) Directive No. 15 Revisions to the Standards for the Classification of Federal Data on Race and Ethnicity (October 30, 1997)

Best Pharmaceuticals Act for Children of 2002 (Public Law 107-109) (February 4, 2002)

NIH PHS Cumulative Inclusion Enrollment Report Form

16